Journal of Medicinal Chemistry
Article
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1-Isopentyl-4-(4-morpholinophenyl)-2-oxopyridine-3-car-
bonitrile (30). Starting from 51a (0.56 g, 2.70 mmol) and 4-
(morpholin-1-yl)phenylboronic acid (0.72 g, 2.7 mmol) and following
the procedure described for 13, compound 30 was obtained as a
yellow solid (0.62 g, 65%), mp 171 °C. 1H NMR (500 MHz, CDCl3)
δ 0.99 (d, J = 6.4 Hz, 6H), 1.62−1.73 (m, 3H), 3.24−3.31 (m, 4H),
3.84−3.90 (m, 4H), 3.95−4.03 (m, 2H), 6.33 (d, J = 6.9 Hz, 1H), 6.96
(d, J = 9.0 Hz, 2H), 7.44 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 9.0 Hz, 2H).
LC−MS m/z 352 [M + H]+, tR = 4.09 min.
solid (0.69 g, 76%). H NMR (500 MHz, CDCl3) δ 0.99 (d, J = 6.4
Hz, 6H), 1.63−1.73 (m, 3H), 2.50 (s, 3H), 3.98−4.05 (m, 2H), 6.31
(d, J = 7.2 Hz, 1H), 6.98−7.03 (m, 2H), 7.19 (dd, J = 8.1, 4.6 Hz, 1H),
7.31 (dd, J = 8.1, 1.2 Hz, 1H), 7.50 (d, J = 6.9 Hz, 1H), 7.59−7.64 (m,
2H), 8.39 (dd, J = 4.8, 1.3 Hz, 1H). LC−MS m/z 374 [M + H]+, tR =
4.12 min.
1-Cyclopropylmehtyl-4-[4-(2-methylpyridin-3-yloxy)-
phenyl]-2-oxo-1,2-dihydropyridine-3-carbonitrile (38). Starting
from 51c (0.39 g, 1.53 mmol) and 57d (0.57 g, 1.83 mmol) and
following the procedure described for 13, compound 38 was obtained
1-Isopentyl-4-[4-(2-methylpyridin-4-ylamino)phenyl]-2-oxo-
1,2-dihydropyridine-3-carbonitrile (31). Starting from 51a
(0.54 g, 1.99 mmol) and 4-(4-pyridylamino)phenylboronic acid
(0.51 g, 2.36 mmol) and following the procedure described for 13,
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as a yellow solid (0.39 g, 72%). H NMR (500 MHz, DMSO-d6) δ
0.38−0.46 (m, 2H), 0.48−0.56 (m, 2H), 1.20−1.32 (m, 1H), 2.39 (s,
3H), 3.83 (d, J = 7.2 Hz, 2H), 6.54 (d, J = 6.9 Hz, 1H), 7.08 (broad d,
J = 9.0 Hz, 2H), 7.34 (dd, J = 8.1, 4.9 Hz, 1H), 7.51 (d, J = 8.1 Hz,
1H), 7.71 (broad d, J = 9.0 Hz, 2H), 8.18 (d, J = 7.2 Hz, 1H), 8.37
(dd, J = 4.6, 1.1 Hz, 1H). LC−MS m/z 358 [M + H]+, tR = 3.67 min.
1-Butyl-4-[4-(2,6-dimethylpyridin-3-yloxy)phenyl]-2-oxo-
1,2-dihydropyridine-3-carbonitrile (39). Starting from 51b
(0.59 g, 2.33 mmol) and 53e (0.91 g, 2.80 mmol) and following the
procedure described for 13, compound 39 was obtained as a pale
yellow solid (0.57 g, 65%). 1H NMR (500 MHz, CDCl3) δ 0.98 (t, J =
7.4 Hz, 3H), 1.35−1.46 (m, 2H), 1.74−1.83 (m, 2H), 2.46 (s, 3H),
2.57 (s, 3H), 4.00 (t, J = 7.4 Hz, 2H), 6.32 (d, J = 6.9 Hz, 1H), 6.95−
7.01 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.50
(d, J = 6.9 Hz, 1H), 7.57−7.63 (m, 2H). LC−MS m/z 374 [M + H]+,
tR = 4.24 min.
1-Isopentyl-4-[4-(2,6-dimethylpyridin-3-yloxy)phenyl]-2-
oxo-1,2-dihydropyridine-3-carbonitrile (40). Starting from 51a
(0.63 g, 2.33 mmol) and 53e (0.91 g, 2.80 mmol) and following the
procedure described for 13, compound 40 was obtained as a pale
yellow solid(0.57 g, 62%). 1H NMR (400 MHz, CDCl3) δ 0.99 (d, J =
6.4 Hz, 6H), 1.61−1.74 (m, 3H), 2.45 (s, 3H), 2.56 (s, 3H), 3.96−4.06
(m, 2H), 6.32 (d, J = 7.0 Hz, 1H), 6.94−7.01 (m, 2H), 7.05 (d, J = 8.3
Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.57−7.63
(m, 2H). LC−MS m/z 388 [M + H]+, tR = 4.54 min.
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compound 29 was obtained as a pale yellow solid (0.25 g, 35%). H
NMR (400 MHz, DMSO-d6) δ 0.94 (d, J = 6.2 Hz, 6H), 1.51−1.64
(m, 3H), 3.93−4.03 (m, 2H), 6.54 (d, J = 7.0 Hz, 1H), 7.03−7.07 (m,
2H), 7.32−7.37 (m, 2H), 7.65−7.70 (m, 2H), 8.12 (d, J = 7.0 Hz,
1H), 8.26−8.31 (m, 2H), 9.21 (s, 1H). LC−MS m/z 359 [M + H]+,
tR = 3.35 min.
1-Isopentyl-4-[4-(2-methylpyridin-4-yloxy)phenyl]-2-oxo-
1,2-dihydropyridine-3-carbonitrile (32). Starting from 51a
(0.74 g, 2.84 mmol) and 53i (0.88 g, 2.84 mmol) and following the
procedure described for 13, compound 32 was obtained as a white
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solid (0.35 g, 36%). H NMR (500 MHz, CDCl3) δ 0.93 (d, J =
6.1 Hz, 6H), 1.57−1.68 (m, 3H), 2.51 (s, 3H), 3.93−4.00 (m, 2H),
6.27 (d, J = 6.9 Hz, 1H), 6.70−6.76 (m, 2H), 7.14 (broad d, J =
8.7 Hz, 2H), 7.47 (d, J = 6.9 Hz, 1H), 7.63 (broad d, J = 8.7 Hz, 2H),
8.35 (d, J = 5.8 Hz, 1H). LC−MS m/z 374 [M + H]+, tR = 4.27 min.
1-Cyclobutylmethyl-4-[4-(2-methylpyridin-4-yloxy)phenyl]-
2-oxo-1,2-dihydropyridine-3-carbonitrile (33). Starting from 51d
(0.56 g, 2.1 mmol) and 53i (0.65 g, 2.1 mmol) and following the
procedure described for 13, compound 33 was obtained as a white
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solid (0.48 g, 62%). H NMR (500 MHz, CDCl3) δ 1.71−1.81 (m,
2H), 1.81−1.95 (m, 2H), 2.00−2.09 (m, 2H), 2.55 (s, 3H), 2.78 (sep,
J = 7.8 Hz, 1H), 3.98 (d, J = 7.5 Hz, 2H), 6.25 (d, J = 6.9 Hz, 1H),
6.75−6.79 (m, 2H), 7.15 (broad d, J = 8.7 Hz, 2H), 7.45 (d, J = 6.9
Hz, 1H), 7.64 (broad d, J = 8.7 Hz, 2H), 8.34−8.38 (m, 1H). LC−MS
m/z 372 [M + H]+, tR = 4.07 min.
1-Cyclopropylmethyl-4-[4-(2,6-dimethylpyridin-3-yloxy)-
phenyl]-2-oxo-1,2-dihydropyridine-3-carbonitrile (41). Starting
from 51c (0.39 g, 1.53 mmol) and 53e (0.6 g, 1.84 mmol) and
following the procedure described for 13, compound 41 was obtained
1-Butyl-4-[4-(2-methylpyridin-4-yloxy)phenyl]-2-oxo-1,2-di-
hydropyridine-3-carbonitrile (34). Starting from 51b (1.44 g, 5.68
mmol) and 53i (1.76 g, 5.68 mmol) and following the procedure
described for 13, compound 34 was obtained as a white solid (0.7 g,
36%), mp 121 °C. 1H NMR (500 MHz, CDCl3) δ 0.92 (t, J = 7.4 Hz,
3H), 1.31−1.39 (m, 2H), 1.69−1.77 (m, 2H), 2.52 (s, 3H), 3.95 (t, J =
7.5 Hz, 2H), 6.27 (d, J = 6.9 Hz, 1H), 6.71−6.77 (m, 2H), 7.15 (broad d,
J = 8.7 Hz, 2H), 7.47 (d, J = 6.9 Hz, 1H), 7.63 (broad d, J = 8.7 Hz, 2H),
8.35 (d, J = 5.8 Hz, 1H). LC−MS m/z 360 [M + H]+, tR = 3.97 min.
1-Cyclopropylmethyl-4-[4-(2-methylpyridin-4-yloxy)-
phenyl]-2-oxo-1,2-dihydropyridine-3-carbonitrile (35). Starting
from 51c (0.48 g, 1.91 mmol) and 53i (1.05 g, 3.39 mmol) and
following the procedure described for 13, compound 35 was obtained
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as a white solid (0.18 g, 31%). H NMR (400 MHz, CDCl3) δ 0.38−
0.50 (m, 2H), 0.61−0.76 (m, 2H), 1.28 (m, 1H), 2.45 (s, 3H), 2.56
(s, 3H), 3.87 (d, J = 7.3 Hz, 2H), 6.29−6.37 (m, 1H), 6.95−7.01
(m, 2H), 7.04 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.58−7.66
(m, 3H). LC−MS m/z 372 [M + H]+, tR = 4.0 min.
1-Butyl-4-[3-chloro-4-(2-methylpyridin-4-yloxy)phenyl]-2-
oxo-1,2-dihydropyridine-3-carbonitrile (42). Starting from 51b
(0.39 g, 1.53 mmol) and 53l (0.57 g, 1.83 mmol) and following the
procedure described for 13, compound 42 was obtained as a white
solid (0.38 g, 63%). 1H NMR (500 MHz, CDCl3) δ 0.99 (t, J = 7.4 Hz,
3H), 1.37−1.46 (m, 2H), 1.76−1.84 (m, 2H), 2.54 (s, 3H), 4.03 (t, J =
7.4 Hz, 2H), 6.33 (d, J = 6.9 Hz, 1H), 6.69 (dd, J = 5.8, 2.6 Hz, 1H),
6.73 (d, J = 2.6 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 6.9 Hz,
1H), 7.62 (dd, J = 8.4, 2.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 8.41 (d,
J = 5.8 Hz, 1H). LC−MS m/z 394 [M + H]+, tR = 4.25 min.
1-Butyl-4-[2-chloro-4-(2-methylpyridin-4-yloxy)phenyl]-2-
oxo-1,2-dihydropyridine-3-carbonitrile (43). Starting from 51b
(0.3 g, 1.17 mmol) and 53j (0.41 g, 1.2 mmol) and following the
procedure described for 13, compound 43 was obtained as a white
solid (0.15 g, 33%). 1H NMR (500 MHz, CDCl3) δ 1.00 (t, J = 7.4 Hz,
3H), 1.43 (broad sex, J = 7.5 Hz, 2H), 1.82 (broad quin, J = 7.6 Hz,
2H), 2.56 (s, 3H), 4.04 (t, J = 7.5 Hz, 2H), 6.30 (d, J = 6.9 Hz, 1H),
6.76 (dd, J = 5.8, 2.6 Hz, 1H), 6.81 (d, J = 2.6 Hz, 1H), 7.10 (dd, J =
8.4, 2.6 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H),
7.54 (d, J = 6.9 Hz, 1H), 8.44 (d, J = 5.5 Hz, 1H). LC−MS m/z 394
[M + H]+, tR = 4.25 min.
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as a white solid (0.33 g, 48%). H NMR (500 MHz, DMSO-d6) δ
0.40−0.47 (m, 2H), 0.49−0.58 (m, 2H), 1.21−1.34 (m, 1H), 2.45 (s,
3H), 3.86 (d, J = 7.2 Hz, 2H), 6.59 (d, J = 6.9 Hz, 1H), 6.84 (dd, J =
5.8, 2.6 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 7.34 (broad d, J = 8.7 Hz,
2H), 7.79 (broad d, J = 8.7 Hz, 2H), 8.22 (d, J = 7.2 Hz, 1H), 8.39 (d,
J = 5.5 Hz, 1H). LC−MS m/z 358 [M + H]+, tR = 3.7 min.
1-Butyl-4-[4-(2-methylpyridin-3-yloxy)phenyl]-2-oxo-1,2-di-
hydropyridine-3-carbonitrile (36). Starting from 51b (0.61 g,
2.41 mmol) and 53d (0.9 g, 2.89 mmol) and following the procedure
described for 13, compound 36 was obtained as a white solid (0.51 g,
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60%), mp 136.7 °C. H NMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.4
Hz, 3H), 1.36−1.46 (m, 2H), 1.75−1.83 (m, 2H), 2.50 (s, 3H), 4.00
(t, J = 7.5 Hz, 2H), 6.31 (d, J = 7.2 Hz, 1H), 6.98−7.03 (m, 2H), 7.18
(dd, J = 8.1, 4.9 Hz, 1H), 7.30 (dd, J = 8.1, 0.9 Hz, 1H), 7.49 (d, J =
7.2 Hz, 1H), 7.59−7.64 (m, 2H), 8.39 (dd, J = 4.6, 1.2 Hz, 1H).
LC−MS m/z 360 [M + H]+, tR = 3.96 min.
1-Butyl-4-[3-chloro-4-(2-methylpyridin-3-yloxy)phenyl]-2-
oxo-1,2-dihydropyridine-3-carbonitrile (44). Starting from 51b
(0.51 g, 2 mmol) and 53f (0.90 g, 2.6 mmol) and following the
procedure described for 13, compound 44 was obtained as a pale
yellow solid (0.54 g, 69%), mp 137.4 °C. 1H NMR (500 MHz, CDCl3)
δ 1.01 (t, J = 7.4 Hz, 3H), 1.39−1.47 (m, 2H), 1.77−1.85 (m, 2H),
1-Isopentyl-4-[4-(2-methylpyridin-3-yloxy)phenyl]-2-oxo-
1,2-dihydropyridine-3-carbonitrile (37). Starting from 51a
(0.64 g, 2.41 mmol) and 53d (0.9 g, 2.89 mmol) and following the
procedure described for 13, compound 37 was obtained as a white
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dx.doi.org/10.1021/jm2016864 | J. Med. Chem. 2012, 55, 2388−2405